It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.

中文翻译：

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Gpr120 选择性激动剂可改善肥胖小鼠的胰岛素抵抗和慢性炎症。

众所周知，ω-3 脂肪酸（ω-3-FAs；也称为 n-3 脂肪酸）可以发挥有效的抗炎作用。ω-3-FA 通常作为鱼制品、膳食补充剂和药物消费，具有许多健康益处，包括降低血浆甘油三酯水平、改善动脉粥样硬化和增加胰岛素敏感性。我们报道 Gpr120 是这些脂肪酸的功能受体，并且 ω-3-FAs 在体内和体外以 Gpr120 依赖性方式产生强大的抗炎、胰岛素增敏作用。事实上，在人类编码 GPR120 的基因 (FFAR4) 中已经描述了易患肥胖和糖尿病的遗传变异。然而，维持 Gpr120 慢性激动所必须消耗的鱼油量太高，不实用，因此，高亲和力小分子 Gpr120 激动剂将具有潜在的临床益处。因此，Gpr120 是制药行业中广泛研究的药物发现目标。Gpr40 是另一种脂质感应 G 蛋白偶联受体，很难识别对 Gpr120 比 Gpr40 具有高度选择性的化合物（参考文献 11）。在这里，我们报告选择性高亲和力、口服、小分子 Gpr120 激动剂 (cpdA) 在体外和体内肥胖小鼠中对巨噬细胞发挥有效的抗炎作用。Gpr120 激动剂治疗高脂饮食喂养的肥胖小鼠可改善葡萄糖耐量、降低高胰岛素血症、增加胰岛素敏感性和减少肝脂肪变性。